Antimicrobial Prophylaxis

Perioperative prophylactic antimicrobial therapy may be defined as the administration of antibiotics in the absence of infection, prior to surgery. The words antimicrobial and antibiotic are often used interchangeably; however, they are not equivalent. An antimicrobial is a general term that refers to a group of drugs that includes antibiotics, antifungals, antiprotozoals, and antivirals; whereas an antibiotic is a drug that is used to treat bacterial infections [1]. The general goal of this form of antimicrobial therapy is to reduce the number of viable bacteria present at the time of surgical incision to a level that normal host defenses can handle, thereby preventing postoperative surgical site infection (SSI) [2-9]. Despite the widespread use and availability of antibiotics, however, postoperative wound infections or SSIs still continue to be a problem in people and animals [9-17]. Although the principles of antimicrobial prophylaxis in surgery have been clearly established, many reports continue to describe inappropriate drug selection and use [2-4,10,18,19]. Strict adherence to the recommended guidelines and avoidance of invalid indications or use of drugs with too broad a spectrum of activity should be eliminated to reduce risk of resistance and treatment failure.

Sources of Contamination

Even with appropriate hair removal, skin preparation, and aseptic technique, all surgical wounds are contaminated [20]. The skin and hair of animals provide the principal source of bacterial contamination entering the surgical wound and it is estimated that 20% of normal canine skin flora remains in situ, deep within the hair follicles, even after appropriate skin preparation [1,9,11,13,16,20-22]. Common bacteria residing on normal canine skin after preoperative preparation include (in order of descending prevalence): Staphylococcus intermedius, coagulase-negative Staphylococcus spp, Bacillus spp., Acinetobacter spp., and Staphylococcus aureus [22]. Clinical studies in the dog have revealed that the skin begins to reinstate its inherent bacteria colonies 90 minutes after aseptic preparation, turning a clean procedure into a clean contaminated surgery (Table 12-1) [1]. It is also contraindicated to clip surgical sites any time before anesthetic induction, as they are 3 times as likely to develop infection owing to superficial skin infection resulting from superficial abrasions and cuts [11]. The risk of infection is the same whether or not the surgical site is clipped 4 hours or more before the induction of anesthesia [11]. Although the risk of SSI is not greater for most non-infected, properly performed gastrointestinal and urogenital procedures, the number and species of bacteria vary and must be considered when selecting an antimicrobial agent [4,11,21]. Each segment of normal bowel, beginning at the stomach, has an incrementally increasing load of bacterial colonies, culminating with the colon and rectum, and the most common pathogens encountered in the gastrointestinal tract are coliforms and anaerobes.

Although hematogenous sources of infection are uncommon, prolonged indwelling venous catheter sites should be inspected, as they pose a source of distant infection that may increase the risk of SSI if undetected. Multiple risk factors for the development of vascular catheter-related infection and bacteria have been identified, which include prolonged duration of catheterization (> 3 days), frequent manipulation of catheters and intravenous lines, improper aseptic insertion and maintenance, the use of transparent plastic dressing, contaminated skin-preparation solution, the location of the catheter, and the use of multilumen catheters [16,21,23-25] Exogenous sources of bacteria are also infrequent, but they still should be considered when dealing with a SSI [6,16,20]. Commonly reported exogenous sources of bacteria in people and animals include: surgical equipment, the operating room, and personnel [13,26,27].

A recent prospective study of postoperative SSIs in dogs and cats revealed "infection/inflammation" and "infected" rate of 5.8% and 3%, respectively [13]. In this particular study, a wound was classified as "infected" if purulent drainage, an abscess, or a fistula was recorded, and a wound was classified as "infected/inflamed" when more than 3 of the following signs were present simultaneously: redness, swelling, pain, heat, serous discharge, and wound dehiscence [13]. These infection rates and definitions are in close agreement with previous studies in dogs and cats and also compare favorably to epidemiologic studies in people [8,9,11,16,28].

Indications

SSIs usually develop within 30 days of a procedure and within 1 year of implant application [21]. To develop a SSI, two main conditions must be present: a bacterial inoculum (> 105 bacteria/gram of tissue) and an environment to support bacterial growth and nutrition. In most cases, the mere presence of bacteria is less important than the level of bacterial growth, as all contaminated wounds do not necessarily become infected [20]. A strong correlation exists, however, between wound contamination and SSI rates, with the rate of infection predictably increasing with increasing wound contamination [8,9,13,17].

Classically, the four categories of wound contamination are the following: clean, clean contaminated, contaminated, and dirty (Table 12-1). Although the classification of wound type is important, it is insufficient by itself to accurately predict infection rates, because of the wide variety of presenting complaints and procedures it encompasses [8,9,13,17]. One prospective study revealed the three major risk factors for increasing the probability of surgical wounds becoming infected: the duration of surgery, increasing number of personnel in the operating room (particularly a problem in teaching hospitals), and a dirty surgical site classification [13]. Risk factors identified for a wound to become "infected/inflamed" include: a prolonged duration of anesthesia, admission to a postoperative intensive care unit, the presence of wound drainage, increasing patient weight, and a dirty surgical site classification [13]. For both "infected" and "infected/inflamed" wounds, antimicrobial prophylaxis was a protective factor, decreasing the rate of infection 6 to 7 times [13]. Additional risk factors from previously reported veterinary epidemiologic studies include: prior irradiation of the surgical site, chronologic age of the animal (dogs older than 8 years), sex (intact males), presence of a concurrent endocrinopathy, existence of distant sites of active infection, presence of abnormal body condition scores, administration of propofol as a part of the anesthetic protocol, the contamination of the surgical wound with more than 105 organisms/gram of tissue, excessive use of electrocautery, presence of foreign material and debris, use of braided or multifilament suture material, and presence of a contaminated surgical suction tip [11,14,16,22,29-32].

In 1941, the American Society of Anesthetists, the forerunner of the American Society of Anesthesiologists (ASA), began to classify patients according to their preoperative physical status [33]. The ASA Physical Status Classification System was initially created with 6 classes, and then a seventh class was added. The modern ASA classification consists of 5 categories and was adopted in 1961 (Table 12-2) [34]. Over the years, many clinical studies have utilized the ASA classification system to stratify patients for morbidity and mortality analysis associated with surgery and anesthesia. In people and in dogs, an ASA classification grade greater than 3 has been shown to be associated with an increased risk of SSI. However, this classification system was meant only to categorize physical status for the purpose of audit and statistical analysis. It was never intended to represent perioperative risk of morbidity for any individual patient, because, as with the surgical wound classification system, many other factors such as the surgical procedure, patient preparation, variability of surgeons and equipment used in different institutions can also affect outcome [34].

Pharmacologic Principles [1,35]

The key factors that determine a drug's delivery to the surgical site include: the absorption, distribution, and elimination characteristics of the selected antimicrobial agent (Fig. 12-1). The disposition of most drugs is split between the central compartment of the vascular system and the tissue compartment, which are composed of less perfused areas, including the interstitial fluid which baths the surgical wound. The concentration of the antimicrobial agent in the interstitial fluid is critical to effective drug efficacy, as most antimicrobials penetrate tissues well but perform poorly in formed tissue exudates and clots.

Figure 12-1. Schematic diagram of a drug’s disposition in the body. PO, Per os; SQ, subcutaneous; IM, intramuscular; IV, intravenous.

Plotting the amount of intravenously administered drug in the central and tissue compartments as a function of time (Fig. 12-2) clarifies the rationale for the general recommendations for perioperative antimicrobial prophylaxis. In the alpha phase, the drug is distributed from the central compartment to the peripheral or tissue compartment. When both compartments are at equilibrium, the beta phase ensues, with the onset of drug elimination. Peak tissue concentrations of the antimicrobials are only achieved once the distribution phase is complete. Therefore, for efficacious antimicrobial prophylaxis, antimicrobial administration should be initiated prior to the surgical incision at the start of the elimination phase, or within 30 minutes to an hour when using a cephalosporin or similar β-lactam antibiotic.

Figure 12-2. Plot of the amount of intravenously administered drug in the central and tissue compartments as a function of time. α, Distribution; β, Elimination.

Following intravenous administration, an antimicrobial must reach a certain concentration to have an antimicrobial effect. The minimum inhibitory concentration (MIC) is defined as the lowest concentration that inhibits visible bacterial growth. Practically, the MIC represents the minimum concentration necessary for an antimicrobial to have an inhibitory effect in the plasma or tissues of the animal. The minimum bacteriocidal concentration (MBC) is defined as the lowest concentration that kills 99.9% of the bacteria and is sometimes also referred to as the minimal lethal concentration (MLC). If a drug has a low MBC to MIC ratio (< 4 - 6) it is referred to as a bacteriocidal drug, because it can be administered in safe doses to achieve high effect or bacterial kill. If a drug has a high MBC to MIC ratio (> 6) it is referred to as a bacteriostatic drug, because safe doses may not be possible to achieve a 99.9 % kill of the bacteria encountered. Depending on the dose administered, a drug may be both bacteriocidal and bacteriostatic. For purposes of perioperative prophylaxis, it is preferred that an antimicrobial be bacteriocidal rather than bacteriostatic to achieve greatest drug efficacy during the operative period.

The recommended dose of an antimicrobial is based on MIC studies performed in animal models of infection. Bacteriocidal antimicrobials are to be administered at 4 to 8 times the MIC for maximal drug efficiency; whereas bacteriostatic antimicrobials are administered at 1 time the MIC throughout the dosing period. Dosing recommendations are also based in part on efficacy studies where antimicrobials were classed as either a concentration or a time-dependent drug. Concentration-dependent drug efficacy (such as aminoglycosides or fluoroquinolones) relies upon achieving one peak concentration above the MIC for successful therapy. After achieving that peak, it is acceptable to allow the drug concentration to fall below the MIC for 8 to 12 hours over a 24-hour period. This is in contrast to time-dependent drug efficacy (such as β-lactams), which is reliant not only on achieving but on maintaining those peak concentrations above the MIC for successful drug therapy throughout the dosing interval.

General Recommendations (Table 12-3)

Timing of Antimicrobial First Dose

The goal of perioperative antimicrobial prophylaxis is to achieve serum and tissue drug concentrations for the duration of the operation that exceed the MIC for organisms likely to be encountered during the operation. Landmark experimental studies in the early 1960s revealed that surgical incision contaminated with Staphylococcus aureus could not be distinguished from incisions that had not been contaminated when antimicrobial agents were administered before the incision [36]. Furthermore, in 1976, Stone et al. demonstrated that the lowest SSI rates in patients undergoing gastrointestinal, biliary, and colon operations occurred when antimicrobial agents were administered within 1 hour before incision [37]. Administration of the first antimicrobial dose after surgery resulted in SSI rates almost identical to those in patients who did not receive prophylaxis [37].

Ideally, based on numerous clinical and experimental studies in people and animals, the antimicrobial agent should be administered as near to the incision time as possible to achieve low SSI rates [28,36-39]. Although research in people has demonstrated that administration of the antimicrobial agent at the time of anesthetic induction is safe and results in adequate serum and tissue drug levels at the time of incision, in veterinary medicine we must take into account the time needed after induction for clipping and surgical preparation, which can be far more extensive and time consuming than in humans. If significant preoperative patient preparation is necessary, the initial dose of an antimicrobial should be delayed past anesthetic induction to more closely approximate 1 hour prior to the start of surgery to ensure appropriate drug concentrations in the peripheral compartments [4,11,19,30,39]. It is also advisable to deliver the entire antimicrobial dose 1 hour prior to applying a tourniquet to ensure local tissue concentrations distad to the vascular occlusion [4].

Duration of Antimicrobial Prophylaxis

The majority of published evidence demonstrates that antimicrobial prophylaxis after wound closure is unnecessary, and most studies comparing single- with multiple-dose prophylaxis have not shown benefit of additional doses [3,5,8,31,40]. The optimal duration of antimicrobial prophylaxis in veterinary surgery is unknown. In people, antimicrobial therapy is often continued for 24 hours beyond surgical wound closure, despite concerns regarding superinfection or selection for antimicrobial resistant pathogens.

Selection of an Antimicrobial Drug [1]

For most routine perioperative prophylaxis, the antimicrobial agents of choice are cephalosporins owing to their efficacy, safety, and cost effectiveness. Cephalosporins belong to the β-lactam family of antimicrobials, which also include the penicillins. Similar to other β-lactam antimicrobials, cephalosporins alter cell wall formation by interfering with bacterial peptidoglycan synthesis by inhibiting the final transpeptidation necessary for cross-links of the cell wall.

Cephalosporins are grouped into "generations" by their antimicrobial properties. The original cephalosporins were designated first generation with more extended-spectrum cephalosporin drugs being developed and sequentially classified as second, third, and fourth. In general, each new generation of cephalosporins has significantly greater gram-negative antimicrobial properties than its predecessor, however, the expense of the cephalosporin also usually increases with the generation bracket.

Specifically, most first generation cephalosporins have a spectrum of activity that includes penicillinase-producing, methicillin-susceptible staphylococci and streptococci. First generation cephalosporins also exhibit activity against Staphylococci spp., Streptococci spp., Escherichia coli, Klebsiella spp., and Proteus mirabilis, but they do not display effectiveness against anaerobic bacteria, Pseudomonas, Enterococcus spp., other Proteus, or Serratia. Second generation cephalosporins display a greater gram-negative spectrum while retaining some activity against gram-positive cocci and, therefore, are the antimicrobial of choice for most enteric and abdominal procedures. Second generation cephalosporins may also be active against some anaerobic bacteria as well as some strains of Enterobacter, E. coli, Klebsiella, Proteus, and Serratia that are resistant to first generation cephalosporins. Third generation cephalosporins exhibit a broad spectrum of activity against gram-negative bacteria but display less activity against Staphylococci and Streptococci species. The newest or fourth generation cephalosporins have a greater spectrum of activity against gram-positive organisms than the third generation cephalosporins. They also are useful and have a greater resistance to β-lactamases than the third generation cephalosporins.

In conclusion, SSIs in people and animals are the most common cause of postoperative morbidity and mortality because they often necessitate additional intervention and expense and prolong hospitalization [7,9,10,12-17,28,30,41-45]. Before considering whether antimicrobial agents are indicated, it is imperative that a surgeon consider the type of surgery to be performed, its expected duration, the potential pathogens that may be encountered, and the immunocompetence of the animal. While antimicrobial agents are an essential tool used to limit the incidence of SSIs and their associated complications, they do not replace good surgical technique, including gentle tissue handling, appropriate suture materials and patterns, and adequate preoperative planning.